北京大学学报（医学版）最新文献

Objective: To systematically investigate the rheumatic disease spectrum associated with anti-PM/Scl antibodies and to clarify their clinical significance in idiopathic inflammatory myopathies (IIM).

Methods: Patients who were tested positive for anti-PM/Scl antibodies by immunoblotting at Peking University People' s Hospital from January 2016 to December 2024 were enrolled. Clinical and immunolo gical data were systematically collected and compared across the subgroups defined by anti-PM/Scl75, anti-PM/Scl100, or dual antibody positivity.

Results: A total of 422 anti-PM/Scl-positive patients were enrolled. Among them, 83.2% (351/422) were diagnosed with connective tissue disease (CTD), 7.8% (33/422) were not diagnosed with CTD, and 9.0% (38/422) had an undetermined clinical diagnosis. Among 422 patients, most commonly represented by IIM (19.7%), systemic sclerosis (SSc, 14.2%), overlap syndrome (11.8%), undifferentiated CTD (UCTD, 10.4%), rheumatoid arthritis (6.9%), Sjögren syndrome (6.4%), and systemic lupus erythematosus (6.2%), the remaining diseases accounting for 24.4%. Within the IIM subgroup, dermatomyositis predominated (74.7%), followed next by anti-synthetase syndrome (21.7%) and immune-mediated necrotizing myopathy (3.6%). Anti-PM/Scl75 antibodies were detected in 52.1% (220/422) of the total patients, anti-PM/Scl100 in 43.6% (184/422), and both in 4.3% (18/422). In the subsequent detailed analysis of the anti-PM/ Scl-positive subgroup, double-positive patients showed a significantly higher prevalence of SSc (38.9% vs. 14.1% vs. 12.0%, P=0.015) and interstitial lung disease (ILD, 70.6% vs. 28.8% vs. 35.4%, P=0.002) than those individuals with single antibody positivity alone. Raynaud phenomenon was observed more frequently in both the double-positive and anti-PM/Scl75-positive groups than in the anti-PM/Scl100-positive group (29.4% vs. 21.3% vs. 10.9%, P=0.007). The measured proportion of peri-pheral CD8⁺ T cells was also higher in double-positive patients (35.9%±14.1% vs. 30.4%±11.2% vs. 26.5%±9.7%, P= 0.008), whereas absolute regulatory T-cell levels were lower in the anti-PM/Scl75-positive group compared directly with the anti-PM/Scl100-positive group [7.6% (5.4%, 10.9%) vs. 9.0% (7.9%, 12.0%) vs. 8.8% (5.2%, 9.7%), P=0.017]. Additionally, co-positivity for anti-PM/Scl and other myositis- specific or myositis-associated antibodies was strongly associated with an increased frequency of ILD (P < 0.05).

Conclusion: Anti-PM/Scl antibodies define a broad disease spectrum encompassing IIM, SSc, overlap syndromes, and UCTD. Dual positivity for anti-PM/Scl75 and anti-PM/Scl100 identifies patients prone to systemic sclerosis and pulmonary involvement, suggesting additive pathogenic effects of the two antibody specificities.

Objective: To explore the effects and the molecular mechanisms of homo sapiens longevity assurance homolog 2 of yeast LAG1(LASS2) dephosphorylation on the biological functions of prostate cancer cells.

Methods: Firstly, we examined the expression profiles of LASS2 by immunohistochemical staining using microarray sections from 90 human patients with prostate cancer; then FLAG-tagged LASS2 plasmid was transferred into HEK 293T cells and phosphorylation sites was detected by mass spectrometry. Furthermore, we constructed five phosphorylation-deficient mutants of LASS2 and stably transfected the variants to human prostate cancer cell line PC-3M-1E8 cell with high metastatic potential. The cell biology functions of LASS2 and its five mutants were studied using growth curve, MTT assay, plate colony formation assay, wound migration assay, matrigel invasion study and flow cytometry; and the effect of LASS2 and its phosphorylation-deficient mutants on the physical interaction between LASS2 and ATP6V0C (C subunit of V0 domain of the vacuolar ATPase), ATP6V0C expression, vacuolar ATPase (V-ATPase) activity, extracellular hydrogen ion concentration and secretion of active matrix metalloproteinase 2(MMP-2) was detected. Finally, we examined the effect of protein phosphatase inhibitor calyculin A on growth, migration and invasion of aggressive prostate cancer cells.

Results: LASS2 levels decreased with increasing Gleason scores of prostate cancer tissues by immunohistochemical staining; moreover, proteome analysis by mass spectrometry had identified that three residues in the C-terminal region of LASS2(Ser-341, Ser-348, and Ser-349) were phosphorylated. Dephosphorylation of LASS2 at serine residue 348 significantly enhanced growth, migration (from 49.11%±5.62% to 74.28%±8.77%, P < 0.001) and invasion (from 129.67±13.65 to 206.67±13.50, P < 0.001) of prostate cancer cells, decreased S phase arrest (from 44.17% to 37.90%, P < 0.05) and inhibited cell apoptosis (from 48.540%±0.269% to 29.700%±0.778%, P < 0.05) in vivo through increasing V-ATPase activity, extracellular hydrogen ion concentration and secretion of active MMP-2. Calyculin A significantly reduced growth and invasion of metastatic human prostate cancer cells.

Conclusion: Phosphorylation of LASS2 is essential for regulation of V-ATPase activity, and serine residue 348 of LASS2 is illustrated to be a key phosphorylation site. Phosphorylated LASS2 inhibits prostate cancer cell invasion via negative regulation of V-ATPase activity and protein phosphatase inhibitors are potential therapeutic strategy in aggressive prostate cancer.

Objective: To explore the serum biomarkers of myopenia in patients with rheumatoid arthritis (RA) via serum proteomic profiling.

Methods: This cross-sectional study recruited active RA patients who either sustained non-myopenic or myopenia state over a 2-year follow-up period and unlabeled liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the serum proteomic profiles. Bioinformatics analyses were then applied to identify differentially expressed proteins between the two groups. Further validation cohort enrolled 102 RA patients (including 51 cases of non-myopenia group and 51 cases of myopenia group) and 51 healthy controls (HC) with age- and gender- matched propensity score at a 1 ∶ 1 ∶ 1 ratio. Enzyme-linked immunosorbent assay (ELISA) was used to verify the expression levels of the candidate protein. Multivariate logistic regression analysis was performed to identify baseline factors associated with myopenia in the RA patients.

Results: Initial proteomic analysis of baseline serum samples from 9 non-myopenia RA patients and 10 myopenia RA patients identified 38 differentially expressed proteins. Among them, inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3) showed a significant upregulation in the myopenia group (log₂FC=2.09) and was consistently detected across all the samples. Subsequent ELISA validation confirmed that the serum ITIH3 level in 102 RA patients was significantly higher than that in 51 HC [(119.4±79.7) mg/L vs. (42.3±16.6) mg/L, P < 0.001], in which both myopenia group and non-myopenia group of the RA patients showed higher levels of serum ITIH3 than the HC group (both P < 0.001). Importantly, the serum ITIH3 level in the 51 patients with myopenia were significantly higher than that in the 51 patients without myopenia [(148.1±94.7) mg/L vs. (90.8±46.6) mg/L, P < 0.001]. After adjustment for confounding covariates including gender, age, disease duration, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), radiological joint destruction and previous treatment, the multivariate Logistic regression analysis showed that the baseline serum ITIH3 level was an independent risk factor for myopenia in the RA patients (OR=1.024, 95%CI: 1.013-1.038, P < 0.001).

Conclusion: This study identifies serum ITIH3 as a significant and independent risk factor for myopenia in patients with RA, which imply that ITIH3 might be a potential biomarker of myopenia. Further longitudinal large-sample multicenter validation is warranted to elucidate the precise role of ITIH3 in the pathophysiology of RA-associated myopenia and the clinical utility in risk stratification and management.

This article reports the diagnosis and therapeutic management of a 53-year-old male with VEXAS syndrome mimicking relapsing polychondritis. The patient presented with multiple subcutaneous nodules and auricular/nasal chondritis. Blood routine examination revealed leukopenia, moderate macrocytic anemia and thrombocytopenia. Inflammatory markers were elevated, including erythrocyte sedimentation rate, C-reactive protein (CRP) and interleukin-6. Serological tests were negative for antinuclear antibody (ANA), anti-extractable nuclear antigen antibody spectrum (ENA), and anti-neutrophil cytoplasmic antibody (ANCA), but positive for anticardiolipin antibodies, anti-β2-glycoprotein Ⅰ anti-bodies, and anti-phosphatidylserine-prothrombin antibodies, and screening revealed no thromboembolic events, with no evidence of infection. Genetic testing confirmed a UBA1 gene mutation in Exon 3, spe- cifically p.Met41Val (c.121A>G). Bone marrow aspiration demonstrated grade Ⅲ bone marrow hyperplasia and vacuolization of myeloid precursors without dyshematopoiesis. A skin biopsy indicated a perivascular lymphocytic infiltrate with focal dense neutrophilic infiltrates, consistent with neutrophilic dermatosis. The consultation with experts from the hematology department indicated that there was currently insufficient evidence for the diagnosis of myelodysplastic syndrome. Based on these findings, a diagnosis of VEXAS syndrome was established, with main involvements of the ears/nasal cartilage, skin, and hematopoietic system. The patient' s condition improved significantly following treatment with high-dose glucocorticoids, intravenous immunoglobulin and ruxolitinib phosphate. Throughout the scheduled follow-up period, the patient showed marked clinical improvement, with resolution of subcutaneous nodules and alleviation of swelling and pain in the auricles and nasal bridge. Hematologic parameters improved significantly, serum inflammatory markers returned to near-normal levels, and both anti-cardiolipin antibody and anti-β2-glycoprotein Ⅰ antibody turned negative. Additionally, the titer of anti-phosphatidylserine-prothrombin antibody decreased substantially. Notwithstanding substantial concerns about thrombotic risk due to positive phospholipid antibodies in the context of ruxolitinib treatment, thrombotic events were avoided with patient compliance to low-dose aspirin therapy. This case highlighted that the male patients aged over 50 years presenting with chondritis, refractory autoinflammatory manifestations, and/or unexplained hematological abnormalities, clinicians should consider bone marrow evaluation and UBA1 gene testing to promptly identify VEXAS syndrome, enabling early personalized treatment and improved outcomes.

This case report describes the diagnostic and therapeutic management of a 70-year-old female patient with rheumatoid arthritis (RA) complicated by necrotizing fasciitis (NF).The patient has a history of RA for over 20 years, without previous standardized diagnosis or treatment.On October 3, 2023, the patient presented with swelling and pain in the bilateral proximal interphalangeal joints, the third metacarpophalangeal joint of the right hand, bilateral wrists, knees, and ankles, accompanied by redness, swelling, pain, and fever in the left gluteal region, perianal area, perineum, and the lateral upper segment of the right thigh. Laboratory tests revealed significantly elevated levels of rheumatoid factor, anti-cyclic citrullinated peptide antibodies, white blood cells, neutrophils, C-reactive protein, and erythrocyte sedimentation rate. CT imaging showed multiple large patchy areas of increased density with blurred margins in the subcutaneous adipose tissue of the bilateral gluteal regions and lower limbs, gluteus maximus muscles, and perineum, along with exudative changes in the subcutaneous adipose tissue of the bilateral lower limbs. Surgical exploration revealed extensive black necrotic tissue, and postoperative pathological examination indicated suppurative changes with abscess formation and inflammatory necrotic tissue, accompanied by local granulation tissue hyperplasia. Bacterial culture identified Staphylococcus aureus. Thus, the diagnosis of RA complicated with NF was confirmed. Following timely surgical intervention and antibiotic therapy, the patient is currently recovering satisfactorily. RA complicated with NF is relatively rare and associated with high mortality and a prolonged disease course. Elderly RA patients undergoing treatment with immunosuppressants, nonsteroidal anti-inflammatory drugs, and biologics should be highly vigilant for the risk of developing NF. Clinicians should enhance their understanding of RA complicated with NF, establish an early diagnosis, provide active treatment, and improve patient prognosis.

Mesonephric-like adenocarcinoma (MLA) in the corpus uteri is a highly aggressive malignant tumor, which is easily confused with other types of endometrial cancer. When the tumor morphology and cellular characteristics are not consistent with the clinical biological behavior, attention should be paid to it. This study is to investigate the clinicopathologic features of MLA in the corpus uteri. Three cases of MLA in the corpus uteri diagnosed in the First Affiliated Hospital of Xi'an Jiaotong University from 2020 to 2023 were studied by clinical data, microscopic features and immunohistochemistry. The related literature was reviewed. The clinical manifestations of the three cases of MLA in the corpus uteri were nonspecific. One case was from our hospital and the other two cases were from other hospitals. The age range was 54-58 years. In the specimen description, there was a diffusely growing mass in the endometrium of the uterus, with an uneven surface and tough texture. The muscle wall was extensively invaded. At low magnification, the tumor cells were arranged in tubular, glandular, papillary, micropapillary and solid growth patterns. At high magnification, the cells lining the lumen were arranged in a single layer, cuboidal or columnar pattern, with mild to moderate atypia, with vesicular nuclei and nuclear furrows. Some of the lumens showed eosinophilic homogeneous pink staining without structural-like material. In the solid area, the cells were plat fusiform, arranged in bundles or whirlpools, with large nuclear atypia and frequent mitotic figures. A large number of intravascular cancer thrombus were observed in all the three cases. The tumor cells were positive for GATA3 and/or thyroid transcription factor-1 (TTF1), diffusely positive for pair box gene 2 (PAX2) and PAX8, and positive for CD10 in some luminal margins. Estrogen receptor (ER) was focal positive, and progesterone receptor (PR) was negative. KRAS mutation was detected in case 1. According to the 2023 updated International Federation of Gynecology and Obstetrics (FIGO) staging guidelines for endometrial cancer, all the three cases were in advanced stage. It is suggested that pathologists should make accurate diagnosis based on morphological manifestations, using a set of matched immunohistochemical markers and necessary molecular tests to avoid misdiagnosis and better guide clinical diagnosis and treatment.

Charcot neuroarthropathy (CN) is a rare but severely disabling complication most commonly seen in patients with longstanding diabetic peripheral neuropathy. CN is characterized by progressive destruction, dislocation, and deformity of the foot and ankle joints, often accompanied by altered biomechanics, chronic ulceration, secondary infection, and, in advanced cases, a high risk of amputation or even mortality. The early clinical presentation of CN is frequently atypical, with mild or painless swelling, warmth, and erythema due to underlying sensory deficits, which can easily lead to misdiagnosis as other rheumatic or autoimmune joint disorders such as rheumatoid arthritis and gout. In this report, we present the case of a 60-year-old woman with a 12-year history of type 2 diabetes mellitus who developed persistent swelling and pain in her left ankle for eight months, along with progressive numbness in her left foot for six months. Her initial laboratory and imaging findings suggested a diagnosis of rheumatoid arthritis combined with gout, resulting in the administration of anti-rheumatic and uric acid-lowering therapies, which proved ineffective. Further diagnostic workup, including advanced imaging modalities, neuroelec-trophysiological testing, and synovial biopsy, ultimately confirmed the diagnosis of diabetic Charcot neuroarthropathy, revealing severe joint dislocation, bone fragmentation, and extensive osteolysis. The patient received comprehensive management, including strict glycemic control, anti-osteoporosis treatment, neurotrophic support, and ultimately underwent left ankle multi-joint fusion surgery. During postoperative follow-up, the patient demonstrated significant improvement in limb function, with no recurrence of ulcers or infection. This case highlights the importance of considering CN in diabetic patients with unilateral, painless joint swelling, deformity, and sensory disturbance. Accurate differential diagnosis from rheu-matic and autoimmune diseases, early recognition, and standardized intervention are crucial to prevent irreversible deformity and reduce the risk of amputation, ultimately improving patient outcomes. Early multidisciplinary management and individualized treatment strategies play a key role in optimizing prognosis for patients with diabetic CN.